Substituted octamethyleneimines

ABSTRACT

THIS DISCLOSURE PERTAINS TO HEXAHYDRO-3-BENZAZONINES, E.G., 9,10-DIMETHOXY-3-METHYL-7-PHENYL-1H-2,3,4,5,6,7HEXAHYDRO-3-BENZAZONINE. THESE COMPOUNDS ARE USEFUL AS CENTRAL NERVOUS SYSTEM STIMULANTS, HYPOTENSIVES AND ANTIINFLAMMATORIES.

United States Patent 3,583,975 SUBSTITUTED OCTAMETHYLENEIMINES I WilliamJ. Houlihan, 15 Raynold Road, Mountain Lakes, NJ. 07046, and Robert E.Manning, 350 Baldwin Road, Parsippany, NJ. 07054 No Drawing. Filed Dec.6, 1965, Ser. No. 511,984 Int. Cl. C0711 35/36, 41/00 US. Cl. 260-239 6Claims ABSTRACT OF THE DISCLOSURE This disclosure pertains tohexahydro-B-benzazonines, e.g., 9,10 dimethoxy 3methyl-7-phenyl-1H-2,3,4,5,6,7- hexahydro-3-benzazonine. These compoundsare useful as central nervous system stimulants, hypotensives andantiinflammatories.

The present invention is directed to pharmaceutically acceptablebenzazonines, particularly therapeutically active 1H 2,3,4,5,6,7hexahydro 3 benzazonines of the formula wherein:

R is either a hydrogen atom (H) methyl; ethyl; lower straight chainalkoxy (preferably having from 1 to 4 carbon atoms), e.g. methoxy,ethoxy, propoxy and butoxy; or, together with R methylenedioxy (OCH -O);R is either a hydrogen atom (H); methyl; ethyl; lower straight chainalkoxy (preferably having from 1 to 4 carbon atoms), e.g. methoxy,ethoxy, propoxy and butoxy; or, together with R, methylenedioxy (O-CH--O);

R is either a hydrogen atom (H); lower straight chain alkyl (preferablyhaving from 1 to 4 carbon atoms), e.g. methyl, ethyl, propyl and butyl;-Y or (CH -Y;

R is lower straight chain alkyl (preferably having from 1 to 4 carbonatoms), e.g. methyl, ethyl, propyl and butyl;

each of R and R is independently, either a hydrogen atom (H), methyl orethyl;

Y is phenyl of the formula each of R R and R is either a hydrogen atom(H); methyl; ethyl; lower straight chain alkoxy (preferably having from1 to 4 carbon atoms), e.g. methoxy, ethoxy, propoxy and butoxy; or,together with its adjacent counterpart, methylenedioxy (O-C-H --O-); andn is either 1, 2 or 3;

and acid additions salts thereof.

It is an object of this invention to provide new pharmaceuticallyacceptable and therapeutically active com- 3,583,975 Patented June 8,1971 wherein each of R, R R, R and R has its aboveascribed meaning, asit does throughout the specification, are key intermediates. These keyintermediates are prepared according to the following reaction scheme:

Steps A and B are efiected sequentially (without separation) to form amixed anhydride IV by admixing ethyl chloroformate (ethylchlorocarbonate) with a keto acid III and triethylamine in chloroform ata temperature from 0 to -15 (1., followed by admixture of ap-phenethylamine V with the resultant (maintained in the sametemperature range).

Step C is a cyclization. It is effected with polyphosphoric acid (PPA)at a temperature from 60 to 0 Alternatively, it may be effected eitherwith from a 0.5 to a 5.0 percent methanolic solution of hydrogenchloride at a temperature from room temperature (20 C.) to reflux orwith an acid, such as para-toluenesulfonic acid, in toluene underreflux.

Step D is etfected by refluxing (with stirring) with lithium aluminumhydride (LAH) in an ether, such as diethylether, dibutylether,tetrahydrofuran and dioxane.

The IX salts IX of compounds II are prepared according to known,well-established procedures from compounds II:

A. R 7 R4 I r1 R X I 3 E RL. '1' g N wherein:

R has its above-ascribed meaning, as it does throughout thespecification; and X is a halogen atom,'e.g. iodine (-I) and chlorine(--Cl). Compounds IX are prepared at room temperature in a solvent, e.g.an ether (diethylether or dioxane), either alone or in combination withanother solvent, e.g. methylene chloride.

Compounds I are prepared from IX Na IX-v I in a solvent system at atemperature from 70 to C. The metal sodium can be replaced by otheralkali metals, e.g. lithium and potassium. As a solvent sysetm forreaction F there may be used lower monoalkylamines (R--NH e.g.methylamine, ethylamine and propylamine; lower dialkylamines (RNI-I-R)wherein each of R and R is, independently, either methyl, ethyl orn-propyl, e.g. dimethylamine; or lower alkylene diamines -NH-(CH -NHR*]wherein each of R" and R* is, independently, either a hydrogen atom,methyl, ethyl or n-propyl, and m is either 2 or 3, e.g.N,N-dimethylethylenediamine.

The acid addition salts of compounds I are prepared according to known,well-established procedures. (See, for example, step E.) Among thepharmaceutically acceptable acid addition salts of compounds I are saltsof organic acids, e.g. tartaric acid; inorganic acids, e.g. hydrochloricacid, hydrobromic acid and sulfuric acid; monobasic acids, e.g. analkanesulfonic acid, such as methanesulfonic acid (H OSO H); dibasicacids, e.g., succinic acid; tribasic'acids, e.g. phosphoric acid andcitric acid; saturated acids, e.g. acetic acid; ethylenicallyunsaturated acids, e.g. maleic acid and fumaric acid; and aromaticacids, e.g. salicyclic acid and arylsulfonic acids, such as=benzenesulfonic acid. The only limitation on the acid se lected is thatthe resulting acid addition salt is pharmaceutically acceptable; theacid does not nullify the therapeutic properties of compounds I.

When R R and/or R is other than a hydrogen atom, C ,..C and/or Crespectively, is an asymmetric carbon atom. Compounds I can'have as manyas three asymmetric carbon atoms; either C C or C can be asymmetricirrespective of the symmetry of the others.

Compounds I thus include optical and geometric isomers, racemates,racemic mixtures and mixtures of optically active isomers. Resolution ofracemates of com pounds. I into their optical antipodes (enantomers) iseffected according to procedures well-known to the artskilled.

.The preparationof particular acid addition salts and the isolation ofchemical individuals, i.e. enantiomers, of compounds I and correspondingacid addition salts do not constitute essential parts of this invention,but the respective products are within the scope of this invention. Themethods employed are known methods. When an optically active compound Iis employed to prepare an acid ad- 4 dition salt, the resulting salt hasthe same stereochemistry as its precursor. Likewise, optically activecompounds I are prepared from corresponding optically active compounds11 and/ or IX. A compound II or a compound IX having an asymmetriccarbon atom is resolved, e.g., by preparing the tartrate from anenantiomer of tartaric acid. Compounds I and their pharmaceuticallyacceptable acid addition salts are CNS-active compounds and are usefulas central nervous system (CNS) stimulants, antidepressants, appetitesuppressants, antihypertensive-hypotensi'ves and anti-infiammatories.They are administered either orally or parenterally in standard dosageforms, e.g. tablets and capsules, in daily does of from 20 tomilligrams.

'Each of the pharmaceutically active compounds of this invention, maybe, e.g. incorporated, for oral administration, in a tablet as the soleactive ingredient. A typical tablet is constituted by from 1 to 3percent binder, e.g. tragacanth; from 3 to 10 percent disnitegratingagent, e.g. corn starch; from 2'to 10 percent lubricant, e.g. talcum;from 0.25 to- 1.0 percent lubricant, e.g.. magnesium stearate; anaverage dosage'o'f active ingredient; and q.s. 100 percent of'filler,e.g. lactose; all percentages being by weight. Tablets are preparedaccording to standard tabletting techniques, which are well-known in theart, employing the necessary amounts of conventional granulatingliquids, e.g. alcohol SD-30 and purified Water. An exemplary tablettingformulaion for the instant active compounds is: Y

Parts Title compound of. Example 11 70 Tragacanth 2 Lactose 19.5 Cornstarch 5 Talcum L.. 3 Magnesium stearate 0.5

Alcohol SD-30, purified water: q.s.

I EXAMPLE 1 N- [2- (p-methoxyphenyl) ethyl] -3-b enzoylpropionamide Adddropwise (over a period of one hour) to a stirred solution 'of 17.8parts (0.10 mole). of 3-benzoylpropionic acid and 10.1 parts (0.10 mole)of triethylamine in parts by volume of chloroform, within thetemperature range of 0 to 5, a solution of 10.8 parts (0.10 mole) ofethylchloroformate in 25 parts by volume of chloroform. Stir theresultant for an additional three hours. To the thus-stirred solution,add dropwise (over a period of fifteen minutes) a chloroform solution of15.1 parts (0.10 mole) of 8-(4-methoxyphenyl)-ethylamine. Stir thethusobtained reaction mixture over night (17 hours); extract same withdilute hydrochloric acid; wash with dilute -so dium carbonate solution;dry over sodium sulfate and evaporate in vacuo. Crystallize the residuefrom benzenepentane to obtain 14 parts of title compound, melting point(M.P.) 96 to 97.

Replacing the 3-benzoylpropionic acid with an equivalent of either3-(p-chlorobenzoyl)propionic acid or 3-(3, S-dimethylbenzoyl)-propionicacid results in the prepara- CHaO Add dropwise (over a period of onehour) to a stirred solution of 34.8 parts (0.30 mole) of levulinic acidand 30.6 parts (0.30 mole) of triethylamine in 175 parts by volume ofchloroform, within the temperature range of to a solution of 32.4 parts(0.30 mole) of ethylchloroformate in 25 parts by volume of chloroform.Stir the resultant for an additional three hours. To the thusstirredsolution, add dropwise (over a period of fifteen minutes) a chloroformsolution of 54.3 parts (0.30 mole) offi-(3,4-dimethoxyphenyl)-ethylamine. Stir the thus-obtained reactionmixture overnight; extract same with dilute hydrochloric acid; wash withdilute sodium carbonate solution; dry over sodium sulfate and evaporatein vacuo. Crystallize the residue from benzene-pentane to obtain 17parts of title compound, M.P. 88 to 90.

Replacing the levulinic acid with an equivalent of either 4-oxohexanoicacid or 4-oxoheptanoic acid results in the preparation, in similarmanner, of the corresponding compound VI.

EXAMPLE 3 N-(2-phenylethyl)-3 -benzoylpropionamide Add dropwise (over aperiod of one hour) to a stirred solution of 44.5 parts (0.25 mole) of3-benzoylpropionic acid and 25.2 parts (0.25 mole) of triethylamine in350 parts by volume of chloroform, within the temperature range of 0 to5, a solutionof 28 parts (0.25 mole) of ethylchloroformate in 50 partsby volume of chloroform. Stir the resultant for an additional threehours. To the thus-stirred solution,' add dropwise (over a period offifteen minutes) a chloroform solution of 30.2 parts (0.25 mole) of2-phenethylamine. Stir the thus-obtained reaction mixture overnight;extract same with dilute hydrochloric acid; wash the dilute sodiumcarbonate solution; dry over sodium sulfate and evaporate in vacuo.Crystallize the residue from benzene-pentane to obtain 25 parts of titlecompound, M.P. 98.

Replacing the 3-benzoylpropionic acid with an equivalent of either3-(3,S-dichlorobenzoyl)propionic acid or 3- (4-ethylbenzoyl)-propionicacid results in the preparation, in similar manner, of the correspondingcompound VI.

EXAMPLE 4 b-pheny1-1,5 ,6,10b-tetrahydropyrrolo [2,1-a] isoquino1iJ1-3(2H) -one Heat a solution of 60 parts of N-(Z-phenylethyl)3-benzoylpropionamide in 600 parts of polyphosphoric acid at 100 for 16hours. Admix the thus-obtained dark brown reaction mixture with waterand chloroform; wash the 5 organic phase with sodium carbonate solution;dry same over sodium sulfate and evaporate under reduced pressure.Filter a solution of the thus-obtained residue in a benzenechloroformmixture through a bed of alumina and evaporate the eluant in vacuo.Crystallize the resultant oil from benzene-pentane to obtain 21 parts ofpure title compound, M.P. 88.

Replacing the N-(Z-phenethyl)-3-benzoylpropionamide with an equivalentof either N-[Z-(p-methoxyphenyl) ethyl] 3-benzoylpropionamide orN-[2-(3,4-dimethoxyphenyl)ethyl]-3-benzoylpropionamide results in thepreparation, in similar manner, of the corresponding compound VII.

EXAMPLE 5 N 2- 3 ,4-dimethoxyphenyl ethyl] -3 -benzoylpropionamide CHaOQW H N CH 0 Add dropwise (over a period of one hour) to a stirredsolution of 17.8 parts (0.10 mole) of B-benzoylpropionic acid and 10.1parts (0.10 mole) of triethylamine in 175 parts by volume of chloroform,within the temperature range of 0 to 5, a solution of 10.8 parts (0.10mole) of ethylchloroformate in 25 parts by volume of chloroform. Stirthe resultant for an additional three hours. To the thus-stirredsolution, add dropwise (over a period of fifteen minutes) a chloroformsolution of 18.1 parts (0.10 mole) of[3-(3,4-dimethoxyphenyl)ethylamine. Stir the thus-obtained reactionmixture overnight; extract same with dilute hydrochloric acid; wash withdilute sodium carbonate solution; dry over sodium sulfate and evaporatein vacuo. Crystallize the residue from benzene-pentane to obtain 12parts of title compound, M.P. 94 to 95.

Replacing the 3-benzoylpropionic acid with an equivalent of3-(3-propylbenzoyl)propionic acid results in the preparation, in similarmanner, of the corresponding compound VI.

EXAMPLE 6 8,9-dimethoxyl0b-phenyl-1,5 ,6,10b-tetrahydropyrrol[2,1-a]isoquinolin-3 (2H)-one specific to the preparation of8,9-dimethoxy-10b-aryl-1,5, 6-10b-tetrahydropyrrolo[2, 1-a]isoquinolin-3 (2H) -ones.

CHsO

CHzO- Add dropwise to a solution of 4.5 parts of lithium aluminumhydride (LAH) in diethylether heated under reflux a solution of 12 partsof 8,9-dimethoxy-lb-phenyl-1,5,6, b-tetrahydropyrrolo[2,l-a]isoquino'lin3(2H) one in tetrahydrofuran (THF). After heating the resultant forseveral hours, add (successively) ethylacetate and Water; filter thereaction mixture. Evaporate the filtrate in vacuo and crystallize theresidue from benzene-pentane to obtain 7 parts of pure title compound,M.P. 95 to 96.

Replacing the 8,9dimethoxy-10b-phenyl-1,5,6,10btetrahydropyrrolo[2,l-a]isoquinolin-3(2H)-onewith an equivalent of 10b-phenyl-1,5,6,IOb-tetrahydropyrrolo[2,1- a]isoquinolin-3(2H)-one results in the preparation, in similar manner, ofthe corresponding compound II.

EXAMPLE 8 8,9-dimethoxy-l0b-phenyl-l ,2,3,5,6,l0b-hexahydr0- pyrrolo [2,1-2.] isoquinoline methiodide /CH3 HaCO EXAMPLE 98,9-dimethoxy-1,2,3,5,6,l0b-hexahydropyrrolo [2,1-a]isoquinolinemethiodide Dissolve 18 parts of8,9-dimethoxy-1,2,3,5,6,IOb-hexahydropyrrolo[2,1-a]isoquinoline[prepared according to the method of Child, R., and Pyman, F. L.,Journal of the Chemical Society, London, 36 (1931)] in an admixture of20 parts by volume of methanol, 80 parts by volume of diethylether and40 parts b volume of methyl iodide. Maintain the resulting solution at 8for 17 hours. Thereafter filter the precipitated crystals andrecrystallize same from methanol to obtain 19 parts of title compound,M.P. 215 to 218.

Replacing the8,9-dimethoxy-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline With anequivalent of either 1-ethyl-9-methoxy 2 methyl1',2,3,5,6,10b-hexahydropyrrolo[2,l-a]isoquinoline or8,9-dimethoxy-2-methyl-1,2,3,5,6,10b-hexahydropyrrol0[2,l-a]isoquinoline results in thepreparation, in similar manner, of the corresponding compound IX.

EXAMPLE 10 HaCO Haco- NCHa Dissolve 8 parts of IOb-benzyl 8,9 dimethoxy:1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline in an admixture of 60parts by volume of diethylether and 20 parts by volume of methyl iodide.Maintain the resulting solution at 8 for 17 hours. Thereafter filter theprecipitated crystals and recrystallize same from methanol to obtain 9parts of title compound, M.P. 205 to 208 Replacing thel0b-benzyl-8,9-dimethoxy1,2,3,5,6,10bhexahydropyrrolo[2,1-a1isoquinoline with an equivalent ofeither lob-(3,5 dimethylbenzyl) 8,9 methylene dioxy 1,2,3,5,6,10bhexahydropyrrolo[Ll-a]isoquinoline or 10b-p-methoxybenzyl 1,2,3,5,6,10bhexahydropyrrolo[2,1-a]isoquinoline results in the preparation, insimilar manner, of the corresponding compound IX.

EXAMPLE 11 9,10-dimethoxy-3-methyl-7-phenyl-1H-2,3,4,5,6,7-hexahydro-S-benzazonine hydrochloride Suspend 8 parts of the titlecompound of Example 8 in 400 parts by volume of liquid ammonia (in aflask immersed in a Dry Ice/acetone bath). Add (with stirring) 2.4 partsof sodium to the resulting suspension. After continuing the stirring foran hour following the sodium addition, permit the obtained reactionmixture to evaporate for 17 hours.

Admix the resulting residue successively with methanol, with water andwith diethylether. Wash the ether phase with Water; dry same over sodiumsulfate; and evaporate. The free base of the title compound is thusobtained as an oil.

To convert said oil to the hydrochloride salt, pass excess hydrogenchloride gas through a diethylether solution of the oil.

Crystallize the thus-obtained hydrochloride from methanolacetone toobtain 5.5 parts of title compound, M.P. 235 to 238 Replacing the titlecompound of Example 8 with an equivalent of either 9-methoxy 1 methyl10b p-tolyl- 1,2,3,5,6,10b hexahydropyrrolo[2,1 a]isoquinolinemethiodide or 1-ethyl-10b-(3,4 methylenedioxyphenyl- 1,2,3,5,6,10bhexahydropyrrolo[Ll-a]isoquinoline methiodide results in thepreparation, in similar manner, of the corresponding acid addition saltof compound 1. Other pharmaceutically acceptable acid addition salts arepre- 9, l -dimethoxy-3-methyl-lH-2,3,4,5,6,7 hexahydro-3- benzazonineYCHa Suspend 15 parts of the title compound of Example 9 in 600 parts byvolume of liquid ammonia (in a flask immersed in a Dry Ice/ acetonebath). Add (with stirring) 4.5 parts of sodium to the resultingsuspension. After continuing the stirring for an hour following thesodium addition, permit the obtained reaction mixture to evaporate for17 hours.

Admix the resulting residue successively with methanol, with water andwith diethylether. Wash the ether phase with water; dry same over sodiumsulfate; and evaporate. Crystallize the resulting oil frombenzene/pentane to obtain 5 parts of pure title compound, M.P. 87 to 88.

Replacing the title compound of Example 9 with an equivalent of either 8methoxy 1,2,l0b trimethyll,2,3,5,6,l0bhexahydropyrrolo[2,l-a]isoquinoline methiodide or 2,10b diethyl1,2,3,5,6,10b hexahydropyrrolo[2,l-a]isoquinoline methiodide results inthe preparation, in similar manner, of the corresponding compound I.

EXAMPLE 13 3-methyl-7-benzyl-9, IO-dimethoxy-1H-2,3,4,5,6,7-hexahydro-3-benzazonine Suspend 9 parts of the title compound of Example10 in 400 parts by volume of liquid ammonia (in a flask immersed in aDry Ice/acetone bath). Add (with stirring) 2.5 parts of sodium to theresulting suspension. After continuing the stirring for an hourfollowing the sodium addition, permit the obtained reaction mixture toevaporate for 17 hours.

Admix the resulting residue successively with methanol, with water andwith diethylether. Wash the ether phase with water; dry same over sodiumsulfate; and evapo rate. Crystallize the resulting oil from methanol andrecrystallize the resulting precipitate from methanol to obtain 3.5parts of title compound, M.P. 94 to 96.

Replacing the title compound of Example 10 with an equivalent of eitherl llb-p-methoxyphenyl 2 methyl- 8,9 methylenedioxy 1,2,3,5,6,10bhexahydropyrrolo- [2,l-a]isoquinoline methiodide or 1,2 diethyl 10b-(3,5 dimethoxybenzyl)-1,2,3,5,6,l0b-hexahydropyrrolo-[2,l-a]isoquinoline methiodide results in the preparation, in similarmanner, of the corresponding compound I.

, 10 What is claimed is: 1. A compound of the formula where:

R is a member selected from the group consisting of a hydrogen atom,methyl, ethyl, lower straight chain alkoxy and, together with Rmethylenedioxy;

R is a member selected from the group consisting of a hydrogen atom,methyl, ethyl, lower straight chain alkoxy and, together with R,methylenedioxy;

Y is a phenyl of the formula n is one of the integers 1, 2 and 3; and

each of R R and R is a member selected from the group consisting of ahydrogen atom, methyl, ethyl, lower straight chain alkoxy and, togetherwith the member on an adjacent carbon atom, methylenedioxy.

2. The compound according to claim 1 which is 3-methyl-7-benzyl-9,IO-dimethoxy lH-2,3,4,5,6,7-hexahydro-3- benzazonine.

3. A process for preparing a compound of the formula which comprisesreacting a compound of the formula wherein n is one of the integers 1, 2and 3;

R is a lower straight chain alkyl;

each of R and R is, independently, a member selected r 7 ReferencesCited 21:52: zlliglgroup consisting of a hydrogen atom, methyl ,2 UNITEDSTATES PATENTS each of R R and R is a member selected from the 3,055,8339/ n 60-239 group consisting of a hydrogen atom, methyl, ethyl, 53,314,963 7- K ch 260--239 lower straight chain alkoxy and, togetherwith the 3,393,192 5 Walter et r 9 member on an adjacent carbon atom,methylenedioxy; FOREIGN PATENTS and X 18 a halogen atom; with an alkalimetal, in liquid ammonia or an amine 2,710M 8/ 96 France 260239 solvent,at a temperature of from --70 C. to 0 C.

10 4. A process according to claim 1 wherein the alkali ALTONROLLINSBnmTary Exammer metal is sodium;

5. A process according to claim 1 wherein the solvent f is liquidammonia. 260-283, 286, 289, 340.5, 558, 559, 561; 424244, 282

6. A process according to claim 1 wherein X is iodine. 15

